Molecule Information

General Information of the Molecule (ID: Mol04058)

• Name: Proprotein convertase subtilisin/kexin type 9 (PCSK9) ,Homo sapiens
• Synonyms: Neural apoptosis-regulated convertase 1; Proprotein convertase 9; Subtilisin/kexin-like protease PC9
• Molecule Type: Protein
• Gene Name: PCSK9
• Gene ID: 255738
• Location: chr1:55039445-55064852[+]
• Sequence:
  MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLAEAPEHGT
  TATFHRCAKDPWRLPGTYVVVLKEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLP
  GFLVKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPPRYRADEYQPPDGGSLV
  EVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAG
  VAKGASMRSLRVLNCQGKGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAA
  CQRLARAGVVLVTAAGNFRDDACLYSPASAPEVITVGATNAQDQPVTLGTLGTNFGRCVD
  LFAPGEDIIGASSDCSTCFVSQSGTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSA
  KDVINEAWFPEDQRVLTPNLVAALPPSTHGAGWQLFCRTVWSAHSGPTRMATAVARCAPD
  EELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAP
  PAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGTHKPPVLRPRGQPNQCVGHREASIHASC
  CHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRD
  VSTTGSTSEGAVTAVAICCRSRHLAQASQELQ
• 3D-structure: PDB ID: 2P4E; Classification: Hydrolase; Method: X-ray diffraction; Resolution: 1.98 Å
• Function: Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments (PubMed:18039658). Acts via a non- proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation (PubMed:17461796, PubMed:18197702, PubMed:18799458, PubMed:22074827). Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway (PubMed:18660751). Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways. .
• Uniprot ID: PCSK9_HUMAN
• Ensembl ID: ENSG00000169174
• HGNC ID: HGNC:20001

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Preclinical Drug(s) 1 drug(s) in total

Arenobufagin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [1]

• Metabolic Type: Lipid metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: Arenobufagin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.96E-09; Fold-change: 4.92E-01; Z-score: 5.99E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cholesterol metabolism; Activation; hsa04979
• In Vivo Model: Hepa1-6 hepatocellular carcinoma transplanted tumor model mice; Mice
• Experiment for Molecule Alteration: Western blot analysis and immunohistochemical assays
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration.

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [1]

• Metabolic Type: Lipid metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: Arenobufagin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.96E-09; Fold-change: 4.92E-01; Z-score: 5.99E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cholesterol metabolism; Activation; hsa04979
• In Vitro Model: Hepa1-6 cells; Liver; Mus musculus (Mouse); CVCL_0327
• Experiment for Molecule Alteration: Western blot analysis and immunohistochemical assays
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration.

Approved Drug(s) 1 drug(s) in total

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [1]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.96E-09; Fold-change: 4.92E-01; Z-score: 5.99E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cholesterol metabolism; Activation; hsa04979
• In Vivo Model: Hepa1-6 hepatocellular carcinoma transplanted tumor model mice; Mice
• Experiment for Molecule Alteration: Western blot analysis and immunohistochemical assays
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration.

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [1]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.96E-09; Fold-change: 4.92E-01; Z-score: 5.99E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cholesterol metabolism; Activation; hsa04979
• In Vitro Model: Hepa1-6 cells; Liver; Mus musculus (Mouse); CVCL_0327
• Experiment for Molecule Alteration: Western blot analysis and immunohistochemical assays
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration.

References

• Ref 1: Arenobufagin modulation of PCSK9-mediated cholesterol metabolism induces tumor-associated macrophages polarisation to inhibit hepatocellular carcinoma progression. Phytomedicine. 2024 Jun;128:155532.